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Kidney stone disease (KSD) is a prevalent condition associated with high morbidity, frequent recurrence, and progression to chronic kidney disease (CKD). The etiology is multifactorial, depending on environmental and genetic factors. Although monogenic KSD is frequent in children, unbiased prevalence data of heritable forms in adults is scarce. Within 2 years of recruitment, all patients hospitalized for urological kidney stone intervention at our center were consecutively enrolled for targeted next generation sequencing (tNGS). Additionally, clinical and metabolic assessments were performed for genotype-phenotype analyses. The cohort comprised 155 (66%) males and 81 (34%) females, with a mean age at first stone of 47 years (4-86). The diagnostic yield of tNGS was 6.8% (16/236), with cystinuria (SLC3A1, SLC7A9), distal renal tubular acidosis (SLC4A1), and renal phosphate wasting (SLC34A1, SLC9A3R1) as underlying hereditary disorders. While metabolic syndrome traits were associated with late-onset KSD, hereditary KSD was associated with increased disease severity in terms of early-onset, frequent recurrence, mildly impaired kidney function, and common bilateral affection. By employing systematic genetic analysis to a less biased cohort of common adult kidney stone formers, we demonstrate its diagnostic value for establishing the underlying disorder in a distinct proportion. Factors determining pretest probability include age at first stone (<40 years), frequent recurrence, mild CKD, and bilateral KSD.

B iallelic pathogenic variants within MAPKBP1, encoding mitogen-activated protein kinase binding protein 1, were recently reported to cause juvenile, late-onset, cilia-independent nephronophthisis ([NPH], Mendelian

Background Congenital abnormalities of the kidney and urinary tract (CAKUT) are characterized by vast phenotypic heterogeneity and incomplete penetrance. Although CAKUT represent the main cause of pediatric chronic kidney disease, only around 20% can be explained by single-gene disorders to date. While pathogenic alterations of PBX1 were recently associated with a severe form of syndromic CAKUT, most CAKUT-patients survive childhood and adolescence to reach end-stage kidney disease later in life. Although somatic mosaicism is known to attenuate severity in other kidney diseases, it has rarely been described nor systematically been assessed in CAKUT. Methods In-depth phenotypic characterization of the index patient and his family. Targeted next-generation sequencing (NGS), segregation analysis, and work-up of mosaicism with DNA isolated from peripheral blood cells, oral mucosa, and cultured urinary renal epithelial cells (URECs). Results Somatic mosaicism was identified in a 20-year-old male with sporadic but mild syndromic renal hypoplasia. He was found to carry a novel de novo truncating variant in PBX1 (c.992C &gt; A, p.(Ser331*)). This variant was detected in 26% of sequencing reads from blood cells, 50% from oral mucosa, and 20% from cultured URECs. Conclusions PBX1 associated CAKUT is characterized by a wealth of de novo mutations. As in de novo cases, mutations can occur intra- or post-zygotically, genetic mosaicism might represent a more common phenomenon in PBX1-disease, accounting for variable expressivity on a general basis. Consequently, we suggest ruling out somatic mosaicism in sporadic CAKUT, notably in attenuated and atypical clinical courses.

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